EHA 2018 | Final analysis of the Phase III GIMEMA Trial

The 23^rd Congress of the European Hematology Association (EHA) took place in Stockholm from 14–17 June 2018 and on Friday 15 June an oral session took place in which Paola Tacchetti from the University of Bologna, Seràgnoli Institute of Hematology, Bologna, Italy, presented the final data from the phase III GIMEMA-MMY-3006 trial. The phase III GIMEMA-MMY-3006 study compared the use of bortezomib (V) on top of a backbone regimen of thalidomide-dexamethasone (TD) with TD alone, before and after double autologous stem-cell transplantation (ASCT), in newly diagnosed multiple myeloma (NDMM) patients. Data from an interim analysis of this study at 36 months was published in The Lancet in 2010, but at the time there was no overall survival (OS) analysis.

Bortezomib-based induction regimens are now widely used as a standard of care (SOC) worldwide, but no trial to date has shown an OS benefit from the inclusion of bortezomib in ASCT protocols. Dr Tacchetti explained that a long-term follow up is necessary in order to determine OS benefits, to explore the possibility of negative effects on therapies further down the line, to assess the emergence of drug-resistant clones, and to evaluate long-term adverse events (AEs) such as secondary primary malignancies (SPMs).

Key Data:

• Patients (pts) were recruited between May 2006 and April 2008
• Cut-off date was May 2018
• VTD was administered in 21 day cycles
• N = 474 pts; VTD = 236 pts, TD = 238 pts
• Median follow-up for surviving pts = 124.1 months (IQR: 117.2-131.7)

Data is given as VTD vs TD:

• Median PFS: 59.6 vs 40.7 months; HR = 0.62, (CI; 0.50-0.77) p<0.0001
• PFS benefit of VTD via sub-group:
  • Age ≤ 60 years: HR = 0.68; (95% CI, 0.516–0.904)
  • Age > 60 years: HR = 0.52; (95% CI, 0.364–0.739)
  • ISS stage I: HR = 0.60, p = 0.005; ISS stage II-III: HR = 0.68, p = 0.007
  • t(4;14) and/or del(17p) positivity: HR = 0.45, p<0.001 negativity: HR = 0.66, p = 0.003
• Time to next treatment (TTnT): 81.3 vs 58.4 months; HR = 0.61 (95% CI, 0.48-0.77) p<0.0001
• Median OS: not yet reached vs 110 months; 60% vs 46%; HR = 0.68, (95% CI, 0.51–0.90) p = 0.007
• OS benefit of VTD via subgroup:
  • Age > 60 years: HR = 0.51, (95% CI, 0.33–0.782)
  • ISS stages III: HR = 0.68, (95% CI, 0.484–0.963)
  • ISS stage I: HR = 0.64, (95% CI, 0.393–1.044)
  • Both t(4;14) and/or del(17p) positivity: HR = 0.54, and negativity: HR = 0.66
• Relapse and progression: total = 64%, VTD = 55%, TD = 73%, p < 0.001
• PFS2 (interval between first and second progression): no significant difference between pts randomized to VTD or TD, or for pts receiving bortezomib as a second line regimen
• OS after first relapse: 52.1 vs  42.3 months (for pts primarily resistant to VTD or TD) and 55 vs 43.9 months (for pts treated with bortezomib 2^nd line regimens)
• SPMs (451 pts with available data): 6.4% vs 10%; p = 0.17

Conclusion

This extensive follow-up of 10 years shows that there is a PFS benefit that extends into a longer TTnT, PFS2, as well as an extended OS in both the overall population and high- and standard- risk subgroups. Following first relapse, the outcomes did not differ significantly, and there was a similar incidence of SPMs. Overall the inclusion of bortezomib into a triplet-based regimen that includes an IMiD along with double ASCT, led to an estimated 10-year PFS of 60%. Ongoing clinical trials are now assessing the benefit of quadruplet combinations upfront.  

Questions

Dr Tacchetti was asked to comment on why the OS curves did not separate between VTD and TD for 4 or 5 years. She explained that it is difficult to explain why but really illustrates the importance of long-term follow-ups. The impressive 10-year PFS of 34% was also commented on and Dr Tacchetti was asked whether they were able to identify the patients that benefit and if after 6 or 7 years they remained in a plateau or relapsed. Dr Tacchetti explained that the majority of patients that had a greater OS had standard cytogenetics and were ISS stage I and that these patients also achieved a complete remission, as well as a complete response. She added that it would be interesting to have data on MRD, but that this is ongoing. Most of these patients have achieved a plateau, but she said that they need to separate out a fraction of patients who have relapsed to see this more clearly.